Functional Restoration of Salivary Glands

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Integrative Biology and Infectious Diseases Branch Division of Extramural Research

OBJECTIVE:

The goal of this initiative is to stimulate multidisciplinary research for restoring damaged salivary gland function by utilizing a variety of approaches, including repair or regeneration of the salivary glands, or replacement with a bioengineered gland.

Loss of salivary gland function is a serious medical problem associated with a number of conditions, including Sjögren’s Syndrome, collateral damage from head and neck radiotherapy, adverse effects from medication use, and age-related atrophy. Restoration of salivary gland function must tackle the underlying mechanisms of tissue damage. Unfortunately, despite a wealth of knowledge generated in basic salivary gland biology, few breakthroughs have been made clinically to restore salivary gland function. Targeted research is needed utilizing cell-, protein/peptide-, small molecule-, gene-, and material-based approaches coupled with bioengineering to advance studies on stimulating fluid secretion. As an example, these studies could concentrate on increasing the activities of channels and transport proteins, or repairing defective acinar and ductal cells in secretory units. In addition, current studies aiming to improve salivary function are hampered by the lack of dynamic tools and reproducible methods to reliably examine salivary function. Therefore, this initiative also encourages the development of such tools for use in animals and humans. Partnering of salivary researchers or secretory biologists with chemists, structural biologists, radiation biologists, stem cell biologists, bioengineers, material scientists or clinical investigators through the use of a multiple-PI project format is critical. Projects must utilize in vivo models, ex vivo multiple tissue constructs and/or in vitro systems to demonstrate structural, molecular and functional restoration; salivary gland performance must be assessed with functional assays and endpoints.

BACKGROUND:

Saliva is essential for maintaining oral homeostasis and serves multiple functions including lubrication, digestion, and host defense. Salivary gland disorders, which cause xerostomia and reductions in salivary flow, increase the risk of dental caries, mucosal infections, dysgeusia, and difficulties in swallowing and speaking, thus compromising the quality of life. The most common disorder involving the salivary glands is Sjögren’s syndrome, an autoimmune disease affecting up to 4 million Americans, mostly middle age women. Approximately 30% of older adults also suffer from xerostomia, in part due to the adverse effects of medications they are using. It is estimated that some 400 medications, including antihistamines, antidepressants and diuretics, are associated with xerostomia as an adverse effect. Although salivary gland tumors are rare, with approximately 3,300 new cases per year, surgical and radiation interventions can destroy the glands. Furthermore, radiation therapy to other head and neck cancers can significantly damage the salivary glands in 40,000 individuals annually. Therefore, salivary gland hypofunction has diverse etiologies, and restoration of function must tackle the underlying mechanisms of tissue damage.

Salivary gland hypofunction significantly compromises the quality of life in millions of Americans through poor oral health and non-compliance with drug treatment of conditions that may cause dry mouth as a side effect. Treatment options are limited and artificial saliva or saliva-stimulating agents are only short-term palliative management. At the forefront is the promising pursuit of a Phase I/II clinical trial of the NIDCR-supported “Open-labeled, dose escalation study evaluating the safety of a single administration of an adenoviral vector encoding human aquaporin-1 to one parotid salivary gland in individuals with irradiation-induced salivary hypofunction”. Otherwise, few breakthroughs have been made clinically to restore salivary gland function, although progress has been made in identifying and characterizing molecular signals, cell-cell and cell-matrix interaction cues for salivary gland differentiation, putative salivary gland stem and progenitor cells, and bioactive scaffolds that may contribute to the design of an artificial salivary gland. In addition, although some studies show structural integrity of repaired or regenerated salivary glands, or tissue-specific gene expression, none has demonstrated an outcome of secretory physiology, such as rate, extent and direction of fluid movement, fluid composition, integrity of tight junction complex, and transepithelial resistance. On the other hand, state-of-the-science technologies and approaches are utilized in the design and regeneration of other organs that could be brought to bear on salivary gland repair. A multidisciplinary approach with an infusion of investigators experienced in soft/glandular tissue repair would propel salivary research to address clinical needs in tangible and meaningful ways.